Glioblastoma is the most common malignant brain tumor of adults and is among the most lethal of all cancers. Deregulation of the PI3K/Akt pathway signaling, which promotes malignant transformation, tumor progression and radiation-resistance in pre-clinical models, is common in glioblastomas. However, its impact on glioblastoma patient survival and response to therapy is not known. Determining the effect of deregulated PI3K pathway signaling on glioblastoma patient survival and response to therapy may potentially translate directly into improved therapy for glioblastoma patients, particularly in light of the availability of specific PI3K signaling pathway specific inhibitors. This proposal brings together the powerful resources of an NCI sponsored multi-institutional cooperative group, the Radiation Therapy Oncology Group (RTOG), with its meticulously characterized clinical samples, and a team of investigators that has demonstrated ability to analyze the activation state of the PI3K pathway in glioblastoma patient samples. This proposal is an important extension of these studies, and it takes full advantage of this important NCI-sponsored resource. The specific aims of this proposal are: Aim 1: We will determine whether activation of the PI3K pathway is associated with diminished survival of glioblastoma patients. Aim 2: We will determine whether activation of the PI3K pathway is associated with radiation resistance in glioblastoma patients. Aim 3: We will identify molecular features of glioblastomas that underlie response to EGFR, mTOR and farnesyl transferase inhibitors under investigation in ongoing and planned RTOG trials to optimize delivery and identify patients who will derive greatest benefit from these biotherapeutic agents.